Received: 16 November 2022

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Revised: 6 July 2023

https://doi.org/10.1016/j.rpth.2023.102160

ILLUSTRATED REVIEW
Accepted: 10 July 2023

New insight into the traditional model of the coagulation

cascade and its regulation: illustrated review of a
three-dimensional view

Romualdo Troisi1,2 | Nicole Balasco3 | Ida Autiero2 | Filomena Sica1 |

Luigi Vitagliano2

1
Department of Chemical Sciences,
University of Naples Federico II, Complesso Abstract
Universitario di Monte Sant’Angelo, Naples,
The coagulation process relies on an intricate network of three-dimensional structural
Italy
2 interactions and subtle biological regulations. In the present review, we illustrate the
Institute of Biostructures and Bioimaging,
CNR, Naples, Italy state of the art of the structural biology of the coagulation cascade by surveying the
3
Institute of Molecular Biology and Protein Data Bank and the EBI AlphaFold databases. Investigations performed in the last
Pathology, CNR c/o Department of
Chemistry, University of Rome Sapienza,
decade have provided structural information on essentially all players involved in the
Rome, Italy process. Indeed, the initial characterization of specific and rather canonical domains has

Correspondence
been progressively extended to complicated multidomain proteins. Recently, the appli-
Filomena Sica, Department of Chemical cation of cryogenic electron microscopy techniques has unraveled the structural features
Sciences, University of Naples Federico II,
Complesso Universitario di Monte
of highly complex coagulation factors, which has led to enhanced understanding. This
Sant’Angelo, Via Cintia, 80126 Naples, Italy. review initially focuses on the structure of the individual factors as a function of their
Email: fi[email protected]
involvement in intrinsic, extrinsic, and common pathways. A specific emphasis is given to
Luigi Vitagliano, Institute of Biostructures what is known or unknown on the structural basis of each step of the cascade. Available
and Bioimaging, CNR, Via Pietro Castellino
111, 80131 Naples, Italy.
data providing clues on the structural recognition of the factors involved in the functional
Email: [email protected] partnerships of the pathways are illustrated. Recent structures of important complexes

Handling Editor: Dr Michelle Sholzberg

formed by these proteins with regulators are described, focusing on the drugs used as
anticoagulants and on their reversal agents. Finally, we highlight the different roles that
innovative biomolecules such as aptamers may have in the regulation of the cascade.

KEYWORDS
anticoagulants, blood coagulation factors, drug interactions, protein conformation, thrombin

Essentials
• Experimental and computational studies have led to an atomic-level understanding of coagulation.
• Key information on the structural aspects of many hemostatic interactions has been elucidated.
• Available data explain the detailed mechanism of action of drugs and reversal agents.
• Structure-based approaches are key to drug optimization.

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© 2023 The Author(s). Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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https://doi.org/10.1016/j.rpth.2023.102160
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